Atherosclerotic cardiovascular disease (ASCVD) remains the primary cause of morbidity and mortality worldwide. Patients with ASCVD represent a heterogeneous group of individuals, with a disease that progresses at different rates and in distinctly different patterns. Despite appropriate evidence-based treatments for patients with ASCVD, recurrence and mortality rates remain 2-4% per year.
In general, atherosclerosis is believed to be a complex disease involving multiple biological pathways. Variations in the natural history of the atherosclerotic disease process, as well as differential response to risk factors and variations in the individual response to therapy, reflect in part differences in genetic background and their intricate interactions with the environmental factors that are responsible for the initiation and modification of the disease. Atherosclerotic disease is also influenced by the complex nature of the cardiovascular system itself where anatomy, function and biology all play important roles in health as well as disease.
Traditional risk factors account for approximately half of an individual's lifetime risk of cardiovascular disease. The balance, therefore, is accounted for by a combination of unmeasured environmental exposures and genetic factors. The recent advent of the genome-wide association study (GWAS) platform has made it possible to investigate the heritable component of complex polygenic disorders, such as atherosclerotic coronary artery disease (CAD). Using this approach, a region on chromosome 9p21.3 has repeatedly been identified in GWAS as the top locus for complex cardiovascular disease (Helgadottir et al. (2007) Science 316:1491-1493; McPherson et al. (2007) Science 316:1488-1491).
Available data suggest that the risk-associated polymorphisms: 1) are very common, with as much as a fifth of the world population carrying two copies of the risk allele (minor allele frequency ˜50%) (Deloukas et al. (2013) Nat Genet 45:25-33); 2) are independent of all established risk factors, suggesting a novel mechanism of action (Cunnington and Keavney (2011) Curr Atheroscler Rep 13:193-201); 3) are responsible for up to 21% of the attributable risk of myocardial infarction (MI); and 4) promote risk across a spectrum of vascular diseases, including CAD, stroke, peripheral artery disease (PAD) and abdominal aortic aneurysm (AAA) (Helgadottir et al. (2008) Nat Genet 40:217-224).
Elucidating the vascular biology of the 9p21 locus has become a priority for the scientific community. Because the most highly associated single nucleotide polymorphisms (SNPs) occur in a noncoding region of the genome, a number of expression quantitative trait locus (eQTL) and allelic expression imbalance (AEI) studies have been performed in an attempt to identify the causal gene(s) which are dysregulated in carriers of the 9p21 risk variant. Though a variety of associations have been reported, reduced expression of the nearby tumor-suppressor gene, CDKN2B, has now been observed in several tissues from carriers of the risk allele, including adipose tissue and circulating cells (Liu et al. (2009) PLoS ONE 4:e5027; Schunkert et al. (2011) Nat Genet 43:333-338), as well as in the ‘end organ’, including atherosclerotic plaque and vascular smooth muscle cells (SMCs), (Pilbrow et al. 2012. PLoS One 7:e39574).
Atherosclerotic plaque consists of accumulated intracellular and extracellular lipids, smooth muscle cells, connective tissue, and glycosaminoglycans. The earliest detectable lesion of atherosclerosis is the fatty streak, consisting of lipid-laden foam cells, which are macrophages that have migrated as monocytes from the circulation into the subendothelial layer of the intima, which later evolves into the fibrous plaque, consisting of intimal smooth muscle cells surrounded by connective tissue and intracellular and extracellular lipids.